The evolution of vertebrate Toll-like receptors

Abstract

The complete sequences of Takifugu Toll-like receptor (TLR) loci and gene predictions from many draft genomes enable comprehensive molecular phylogenetic analysis. Strong selective pressure for recognition of and response to pathogen-associated molecular patterns has maintained a largely unchanging TLR recognition in all vertebrates. There are six major families of vertebrate TLRs. This repertoire is distinct from that of invertebrates. TLRs within a family recognize a general class of pathogen-associated molecular patterns. Most vertebrates have exactly one gene ortholog for each TLR family. The family including TLR1 has more species-specific adaptations than other families. A major family including TLR11 is represented in humans only by a pseudogene. Coincidental evolution plays a minor role in TLR evolution. The sequencing phase of this study produced finished genomic sequences for the 12 Takifugu rubripes TLRs. In addition, we have produced >70 gene models, including sequences from the opossum, chicken, frog, dog, sea urchin, and sea squirt.

Fig. 1.

Molecular tree of the vertebrate TLR. Branches of each major family are shown in a unique color. TLR16 may belong in the TLR11 family; TLR15 may belong in the TLR1 family. “Xenopus” without a species name indicates X. tropicalis. The species is listed along the branch for subfamilies with only one member. To avoid crowding, some known TLRs are not displayed. Bootstrap values <90 are shown as percentages; the preponderance of bootstrap values are 100%. The few low bootstrap values present tend to be associated with uncertainties in placement of very divergent TLRs (e.g., TLR16) or with very short branches.

Fig. 2.

Multidimensional scaling (MDS) of the molecular distances between TLRs. The distance between the gene families compared with the distances within the gene families is so great that portraying this information as a molecular tree could be misleading. Note that, like geographical maps of intercity distances, MDS representations have no axes. Not all TLRs are shown (e.g., Strongylocentrotus has hundreds of TLRs that cluster together).

Fig. 3.

Order and orientation of genes syntenic to (A) TLR4,(B) TLR7 and TLR8,(C) TLR12, and (D) TLR1. For unfinished genomes, a small possibility exists that any gene portrayed as absent is actually present. Orthologs are identified by the Human Genome Organisation (HUGO) symbol of the human ortholog. Klotho Beta in humans is GeneID no. 152831. Genes are intentionally aligned in columns to facilitate visualization of synteny. Such alignments help confirm orthology. Select genomes are chosen to illustrate the dynamics of each locus.